Work by our group using I23I]beta-CIT SPECT has shown increased (about 25%) levels of dopamine transporters (DAT) in acutely abstinent (< 96 h) cocaine addicts as compared to healthy controls. These elevations persist 2-4 weeks after cessation of cocaine use and only gradually normalize with much longer drug- free intervals (3-18 months). These clinical results are consistent with preclinical research indicating long term behavioral and biochemical changes following chronic cocaine administration. For example, two widely discussed phenomena deriving from studies of cocaine addiction are sensitization and abstinence. Sensitization has been most commonly associated with a hyper-dopaminergic state, while abstinence is hypothesized to derive from a state of dopamine (DA) deficiency. These two major neurobiological hypotheses of addiction remain largely untested in clinical populations of human cocaine abusers. We and other imaging groups have developed paradigms to indirectly measure the release of DA by its ability-to displace radiotracer binding at D2 receptors. Sensitization to chronic amphetamine or cocaine administration in animals has frequently been associated with increased DA release as measured by microdialysis. We will assess the existence of sensitization in cocaine addicts using an [123I]IBzM-amphetamine SPECT imaging paradigm (Aim #1). Amphetamine is generally thought to act by making the membrane transporter work in reverse to release DA into the synapse. Thus, an enhanced amphetamine response may be associated with elevated DAT levels in cocaine abusers. Conversely, preliminary SPECT studies in healthy human subjects suggest the feasibility of in vivo, measures of basal neurotransmitter levels after DA depletion with alpha-methyl-para-tyrosine (AMPT). This [123I]lBzM-AMPT paradigm my be a valuable tool for verifying in cocaine abusers rodent microdialysis findings of decreased basal DA. Thus, we propose to develop, optimize, and validate a paradigm of DA depletion (using ANiPT and/or reserpine) combined with D2 receptor imaging to measure basal levels of synaptic DA (Aim #2). Basal levels of synaptic DA will then be assessed in abstinent cocaine addicts using the optimal depletion paradigm(Aim #3).